Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice

Arunika Mukhopadhaya, Tadashi Hanafusa, Irene Jarchum, Yi Guang Chen, Yoshiko Iwai, David V. Serreze, Ralph M. Steinman, Kristin V. Tarbell, Teresa P. DiLorenzo

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet β cells. Cytotoxic CD8+ T cells, reactive to β cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8+ T cells specific for β cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8+ T cell clone AI4, to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with β cell antigens leads to deletion of autoreactive CD8+ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)6374-6379
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number17
DOIs
StatePublished - Apr 29 2008

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Inbred NOD Mouse
Dendritic Cells
T-Lymphocytes
Antigens
Type 1 Diabetes Mellitus
Autoimmune Diseases
Central Tolerance
Peripheral Tolerance
Peptides
Autoantigens
Autoimmunity
Islets of Langerhans
Clone Cells
Infection

Keywords

  • Autoimmune disease
  • Type 1 diabetes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. / Mukhopadhaya, Arunika; Hanafusa, Tadashi; Jarchum, Irene; Chen, Yi Guang; Iwai, Yoshiko; Serreze, David V.; Steinman, Ralph M.; Tarbell, Kristin V.; DiLorenzo, Teresa P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 17, 29.04.2008, p. 6374-6379.

Research output: Contribution to journalArticle

Mukhopadhaya, Arunika ; Hanafusa, Tadashi ; Jarchum, Irene ; Chen, Yi Guang ; Iwai, Yoshiko ; Serreze, David V. ; Steinman, Ralph M. ; Tarbell, Kristin V. ; DiLorenzo, Teresa P. / Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 17. pp. 6374-6379.
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